PROJECT SUMMARY/ABSTRACT The overall goal of this proposed project is to identify rare genetic variants contributing to childhood onset- Crohn disease. Crohn disease is a chronic inflammatory disorder of the gastrointestinal tract of unclear etiology and no known cure. Affected children suffer from diarrhea, abdominal pain, growth disturbances, and an impaired quality of life. The identified Crohn disease susceptibility alleles have improved our understanding of Crohn disease pathogenesis. However, the identified susceptibility alleles do not account for the observed heritability, nor have disease-causing alleles in many genomic regions been identified. For the proposed studies, we will use 1) existing DNA samples collected from high-risk Crohn kindreds identified using the extensive genealogical records available only in Utah, 2) existing DNA samples obtained from very young children with Crohn disease and their parents, and 3) existing DNA samples obtained from healthy controls that are free of a personal or family history of autoimmune disorders. Our overall hypothesis is that childhood- onset Crohn disease is caused in part by rare disease susceptibility alleles. In Aim 1, we will perform shared genomic segment analysis and exome sequencing in children in high-risk Crohn disease kindreds. In Aim 2, we will perform targeted re-sequencing studies and a case-control study in which the cases are very young children with Crohn disease. In Aim 3, we will test the hypothesis that, as a consequence of the evolutionary forces, Crohn disease susceptibility alleles have hitchhiked on a previously identified disease risk haplotype in which the disease-causing variant(s) remains unknown. In this proposal, we will use a novel and powerful resource, the Utah Population Database, and further develop innovative analytical strategies to perform gene- mapping studies in large kindreds. We will utilize a phenotypic extreme-childhood-onset Crohn disease-to characterize the rare genetic variation in known susceptibility alleles. Finally, we will explore the evolutionary forces shaping a Crohn disease susceptibility locus, which may provide insight into the disease-causing gene. These studies will improve our understanding of the causes of Crohn disease, help develop clinically useful molecular classification schemes, and lead to improved therapy.